Cytomegalovirus (CMV) infection represents a major health concern in the immunocompromised population, especially recipients of bone marrow and solid-organ transplants. The current standard for therapy is ganciclovir (GCV), and its prodrug valGCV, both of which suffer from bone-marrow toxicity and emerging resistance. Alternatives include Foscarnet (PFA) and cidofovir (CDV), however, toxicity limits their use. Therefore, there is still a need for new anti-HCMV therapeutic agents. A new series of purine nucleoside analogs, the methylenecyclopropanes (MP), have been shown to be potent inhibitors of CMV. In our SBIR Phase II studies, a second generation analog, ZSM-I-62, was shown to be very potent against murine CMV (MCMV) and human CMV (HCMV), including GCV and PFA resistant clinical isolates, and very active against other beta- and gamma-herpes viruses, including HHV 6 and HHV 8. Coupled with its excellent oral bioavailability (58%), ZSM-I-62 was highly efficacious orally (58% oral bioavailability) against murine and human CMV in four experimental animal models. Microbiotix, Inc. owns an exclusive worldwide license from Wayne State University to all the MP compounds and their uses. The primary project objective is to develop ZSM-I-62 for the intravenous (IV) and oral treatment of human CMV infection. HHV 6 and 8 will be secondary clinical therapeutic endpoints. As part of the original SBIR Phase II grant Microbiotix conducted toxicology and pharmacokinetic studies using oral administration. ZSM-I-62 was extremely well tolerated in both the rat and dog oral toxicology studies. At the high oral dose in the dog toxicology studies (300mg/kg), the kidney was identified as a potential target organ. Analysis of the SBIR Phase II data further indicated sex, species and dose-related changes in pharmacokinetics. Therefore as outlined in this application, additional IV ZSM-I-62 rat and dog studies will be performed in order expand the pharmacokinetic and toxicology data to effectively establish endpoints required to monitor human clinical safety. The NIH RAID program is supplying ZSM-I-62, including radiolabeled material, formulation support and analytical method development. The goal of this SBIR Phase II Renewal is to expand the IV preclinical IND enabling toxicological profile of ZSM-I-62 and file an Investigational New Drug (IND) application for the IV and oral treatment of HCMV infection. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) infection represents a major health concern in the immunocompromised population. ZSM-I-62 is a novel anti-HCMV agent which has been shown to be very potent against human CMV (HCMV), including drug resistant clinical isolates, orally bioavailability (58%), highly efficacious against HCMV in animal models and extremely well tolerated in rat and dog oral toxicology studies. The goal of this SBIR Phase II Renewal is to prepare an expanded IV preclinical biological profile of ZSM-I-62 for its further development and file an Investigational New Drug (IND) application for the IV and oral treatment of HCMV infection.